Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation
Introduction
Clinical data show that human spinal cord injury (SCI) is accompanied by profound immunological impairment (Cruse et al., 1993, Nash, 2000). Undoubtedly, immune dysfunction after SCI contributes to the significant increase in mortality caused by septicemia, diseases of the lung (e.g., pneumonia), gastrointestinal tract or urinary system (DeVivo et al., 1989). SCI-induced deficiencies in supraspinal control of the sympathetic nervous system (SNS) or hypothalamic–pituitary–adrenal (HPA) axis have long been suspected, but never proven, as mechanisms of post-traumatic immune suppression (Cruse et al., 1996, Nash, 2000).
Activation of the HPA axis causes release of cortisol (humans) or corticosterone (CORT; rodents) from the adrenal cortex into the bloodstream. High or sustained levels of CORT suppress antibody production, cytokine synthesis and leukocyte proliferation (Munck et al., 1984, Barnes, 1998, Moraska et al., 2000). In humans, urinary cortisol remains elevated for months after SCI (Campagnolo et al., 1999) suggesting prolonged dysregulation of HPA function. Activation of the SNS causes the release of norepinephrine (NE). In spleen and lymph nodes, noradrenergic nerves synapse on T and B cells (Felten et al., 1987, Felten and Olschowka, 1987). This “hardwiring” between the spinal cord and lymphoid tissue ensures proper immune function. Indeed, depletion of noradrenergic neurons suppresses antibody synthesis (Kohm and Sanders, 1999). This deficit is overcome by activating B cells in the presence of β2-adrenergic receptor (β2AR) agonists (e.g., terbutaline) (Podojil and Sanders, 2003). However, repeated or prolonged exposure of B cells to NE or other β2AR agonists is immunosuppressive (Melmon et al., 1974, Keller et al., 1983, Maisel, 1994, Harris et al., 1995, Woiciechowsky et al., 1998, Prass et al., 2003).
HPA/SNS responses are coordinated in the spinal cord via supraspinal projections and by afferent feedback from the periphery to sympathetic preganglionic neurons (SPNs) (Hayes et al., 1991, Taylor and Weaver, 1993). SPNs found throughout the thoracic spinal cord (T3–13; Strack et al., 1989, Cano et al., 2001) influence immune function through post-ganglionic noradrenergic projections to spleen (Wan et al., 1993) and adrenal cortex (Bloom et al., 1988, Engeland, 1998). Because SPNs are influenced by descending input from the brain, we predicted that high-level SCI would cause greater dysfunction of the HPA axis and SNS and subsequently, greater immunological impairment than lower level SCI. To test this, mice were subjected to high (T3) vs. mid-thoracic (T9) SCI; after which, circulating CORT, splenic NE and antigen-specific antibody responses were measured as indices of HPA activation and SNS and immune function, respectively. The data show that only after T3 SCI is splenic NE elevated and immune function suppressed. Moreover, the immunological impairment that occurs in T3 SCI mice can be overcome by pharmacological blockade of β2ARs, implicating NE in post-traumatic immune suppression. These studies are of potential clinical significance and could dramatically influence the design of prophylactic or therapeutic vaccines. Indeed, the ability to eradicate extracellular pathogens (Luster et al., 1993, Robbins et al., 1995) or mount an immune response against CNS proteins (e.g., myelin inhibitory proteins) (Huang et al., 1999, Hauben et al., 2001) requires the coordinated activity of T and B cells, dendritic cells and their associated cytokine networks. Here we show that each of these parameters is affected by SCI in a level-dependent fashion.
Section snippets
Mice
Adult pathogen-free C57BL/6 female mice (6–8 weeks old; 16–21 g) were purchased from Taconic Laboratories (Germantown, NY). All experimental procedures described below were approved by the Animal Review Committee at Ohio State University and are in accord with the US Department of Health, Education, and Welfare.
Spinal cord injury
A total of 82 mice received a spinal cord injury (SCI) as described below. Mice were anesthetized (i.p.) with a cocktail of ketamine (80 mg/kg)/xylazine (40 mg/kg), then given
SCI activates the HPA axis but disrupts circadian CORT synthesis
Previously, we demonstrated SCI-induced elevations of serum CORT in a rat model of SCI (Popovich et al., 2001). Here, we extend those findings to mice using a similar model of spinal contusion injury. Specifically, serum CORT was elevated in T9 SCI mice by 1 day post-injury (dpi), with levels returning toward baseline by 3 dpi (Fig. 1A). To determine whether SCI affected the circadian regulation of circulating CORT, sera were obtained from T9 spinal contusion-injured mice at regular intervals
Discussion
Here we show that immune suppression after SCI is level dependent and involves NE acting at β2ARs. Indeed, only in mice with high-level (T3) SCI was the concentration of splenic NE increased and antibody synthesis decreased relative to sham-injured or T9 SCI mice. Although the precise mechanism of immune suppression remains unclear, our results implicate aberrant β2AR-mediated signaling in lymphocytes. Indeed, only in T3 SCI mice was increased splenocyte apoptosis noted and immune suppression
Acknowledgments
The authors thank Ming Wang, Zhen Guan, Pat Walters, Violeta McGaughy and Susan Moseley for their technical assistance. The authors also thank Daniel Ankeny, Kristina Kigerl and Dana McTigue for their critical review. Funding was provided by NIH T32 AI55411 (KML), NIH AI37326 (VMS), NIH NS047175 (PGP) and P30-NSO45758.
References (57)
- et al.
A comparison of commercially available adjuvants for use in research
J. Immunol. Methods
(1992) - et al.
Apoptotic signaling through the beta-adrenergic receptor. A new Gs effector pathway
J. Biol. Chem.
(2000) - et al.
Effect of prolonged catecholamine infusion on immunoregulatory function: implications in congestive heart failure
J. Am. Coll. Cardiol.
(1995) - et al.
A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord
Neuron
(1999) - et al.
Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests
Fundam. Appl. Toxicol.
(1993) - et al.
Prolonged alpha-adrenergic stimulation causes changes in leukocyte distribution and lymphocyte apoptosis in the rat
J. Neuroimmunol.
(2001) - et al.
CNS cell groups regulating the sympathetic outflow to adrenal gland as revealed by transneuronal cell body labeling with pseudorabies virus
Brain Res.
(1989) - et al.
Spinal cord injury triggers systemic autoimmunity: evidence for chronic B lymphocyte activation and lupus-like autoantibody synthesis
J. Neurochem.
(2006) Anti-inflammatory actions of glucocorticoids: molecular mechanisms
Clin. Sci. (Lond.)
(1998)- et al.
The adrenal contribution to the neuroendocrine responses to splanchnic nerve stimulation in conscious calves
J. Physiol.
(1988)
Alteration of immune system function in tetraplegics. A pilot study
Am. J. Phys. Med. Rehabil.
Impaired phagocytosis of Staphylococcus aureus in complete tetraplegics
Am. J. Phys. Med. Rehabil.
Adrenal and pituitary hormone patterns after spinal cord injury
Am. J. Phys. Med. Rehabil.
Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing
J. Comp. Neurol.
Ventilator-associated pneumonia
Am. J. Respir. Crit. Care Med.
Neuroendocrine-immune interactions associated with loss and restoration of immune system function in spinal cord injury and stroke patients
Immunol. Res.
Decreased immune reactivity and neuroendocrine alterations related to chronic stress in spinal cord injury and stroke patients
Pathobiology
Immune system-neuroendocrine dysregulation in spinal cord injury
Immunol. Res.
Agonist-promoted high affinity state of the beta-adrenergic receptor in human neutrophils: modulation by corticosteroids
J. Clin. Endocrinol. Metab.
Sympathetic abnormalities during autoimmune processes: potential relevance of noradrenaline-induced apoptosis
Ann. N. Y. Acad. Sci.
Cause of death for patients with spinal cord injuries
Arch. Intern. Med.
Functional innervation of the adrenal cortex by the splanchnic nerve
Horm. Metab Res.
Bacterial colonization patterns in mechanically ventilated patients with traumatic and medical head injury. Incidence, risk factors, and association with ventilator-associated pneumonia
Am. J. Respir. Crit. Care Med.
Noradrenergic sympathetic innervation of the spleen: II. Tyrosine hydroxylase (TH)-positive nerve terminals form synapticlike contacts on lymphocytes in the splenic white pulp
J. Neurosci. Res.
Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp
J. Neurosci. Res.
Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: comparison with other myelin antigens
Proc. Natl. Acad. Sci. U. S. A.
Evidence for descending tonic inhibition specifically affecting sympathetic pathways to the kidney in rats
J. Physiol.
Splenic contraction, catecholamine release, and blood volume redistribution during diving in the Weddell seal
J. Appl. Physiol.
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